The New England Journal of Medicine ©Copyright, 1990, by the Massachusetts Medical Society Volume 323 JULY 5, 1990 Number 1 EFFECTS OF HUMAN GROWTH HORMONE IN MEN OVER 60 YEARS OLD Daniel Rudman, M.D., Axel G. Feller, M.D., Hoskote S. Nagraj, M.D., Gregory A. Gergans, M.D. Pardee Y. Lalitha, M.D., Allen F. Goldberg, D.D.S., Robert A. Schlenker, Ph.D., Lester Cohn, M.D., Inge W. Rudman, B.S., and Dale E. Mattson, Ph.D. Abstract Background. The declining activity of the growth hormone-insulin-like growth factor I (IGF-I) axis with advancing age may contribute to the decrease in lean body mass and the increase in mass of adipose tissue that occur with aging. Methods. To test this hypothesis, we studied 21 healthy men from 61 to 81 years old who had plasma IGF-I concentrations of less than 350 U per liter during a six-month base-line period and a six-month treatment period that followed. During the treatment period, 12 men (group 1) received approximately 0.03 mg of biosynthetic human growth hormone per kilogram of body weight sub- cutaneously three times a week, and 9 men (group 2) re- ceived no treatment. Plasma IGF-I levels were measured monthly. At the end of each period we measured lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at nine skeletal sites. Results. In group 1 , the mean plasma IGF-I level rose into the youthful range of 500 to 1500 U per liter during treatment, whereas in group 2 it remained below 350 U per liter. The administration of human growth hormone for six months in group 1 was accompanied by an 8.8 percent increase in lean body mass, a 14.4 percent decrease in adipose-tissue mass, and a 1.6 percent increase in aver- age lumbar vertebral bone density (P<0.05 in each in- stance). Skin thickness increased 7.1 percent (P = 0.07). There was no significant change in the bone density of the radius or proximal femur. In group 2 there was no signifi- cant change in lean body mass, the mass of adipose tis- sue, skin thickness, or bone density during treatment. Conclusions. Diminished secretion of growth hor- mone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thin- ning of the skin that occur in old age. (N Engl J Med 1990; 323:1-6.) IN middle and late adulthood all people experience a series of progressive alterations in body composi- tion. 1 The lean body mass shrinks and the mass of adipose tissue expands. The contraction in lean body mass reflects atrophic processes in skeletal muscle, liv- er, kidney, spleen, skin, and bone. These structural changes have been considered un- avoidable results of aging. 1 It has recently been pro- posed, however, that reduced availability of growth hor- mone in late adulthood may contribute to such changes. 1 ' 2 This proposal is based on two lines of evi- dence. First, after about the age of 30, the secretion of growth hormone by the pituitary gland tends to de- cline. 1 ' 3 ' 4 Since growth hormone is secreted in pulses, mostly during the early hours of sleep, it is difficult to From the Department of Medicine, Medical College of Wisconsin, Milwaukee (D.R., I.W.R.); the Medical Service, Veterans Affairs Medical Center, Milwaukee (D.R.); the Department of Medicine, Chicago Medical School, North Chicago (A.G.F., H.S.N., GA.G., P.Y.L., L.C.); the Medicine (A.G.F., H.S.N., P.Y.L.), Nu- clear Medicine (GA.G), and Dental (A.F.G) Services, Veterans Affairs Medical Center, North Chicago; the Argonne National Laboratory, Argonne, 111. (R.A.S.); and the Epidemiology-Biometry Program, University of Illinois School of Public Health, Chicago (D.E.M.). Supported by grants from the Department of Veterans Affairs and Eli Lilly and Co., and by a grant (1D31 PE95008-02) from the Public Health Service. measure the 24-hour secretion of the substance direct- ly. Growth hormone secretion can be measured indi- rectly, however, by measuring the plasma concentration of insulin-like growth factor I (IGF-I, also known as so- matomedin C), which is produced and released by the liver and perhaps other tissues in response to growth hormone. 1 There is little diurnal variation in the plas- ma IGF-I concentration, and measurements of it are therefore a convenient indicator of growth hormone se- cretion. 1 Plasma IGF-I concentrations decline with ad- vancing age in healthy adults. 1 ' 4 ' 6 Less than 5 percent of the healthy men 20 to 40 years old have plasma IGF-I values of less than 350 U per liter, but the values are below this figure in 30 percent of the healthy men over 60. 4 Likewise, the nocturnal pulses of growth hor- mone secretion become smaller or disappear with ad- vanced age. If the plasma concentration of IGF-I falls below 350 U per liter in older adults, no spontaneous circulating pulses of growth hormone can be detected by currently available radioimmunoassay methods. 4 The concomitant decline in plasma concentrations of both hormones supports the view that the decrease in IGF-I results from diminished growth hormone secre- tion. 4 ' 6 Second, diminished secretion of growth hor- Downloaded from www.nejm.org on December 01 , 2003. Copyright© 1990 Massachusetts Medical Society. All rights reserved. THE NEW ENGLAND JOURNAL OF MEDICINE July 5, 1990 mone is accompanied not only by a fall in the plasma IGF-I concentration, but also by atrophy of the lean body mass and expansion of the mass of adipose tis- sue. 1 These alterations in body composition caused by growth hormone deficiency can be reversed by re- placement doses of the hormone, as experiments in rodents,' children, 8 ' 9 and adults 20 to 50 years old 10 " 13 have shown. These findings suggest that the atrophy of the lean body mass and its component organs and the enlargement of the mass of adipose tissue that are characteristic of the elderly result at least in part from diminished secretion of growth hormone. 1 ' 2 If so, the age-related changes in body composition should be correctable in part by the administration of human growth hormone, now readily available as a biosyn- thetic product. 14 In this study we administered biosynthetic human growth hormone for six months to 12 healthy men from 61 to 81 years old whose plasma IGF-I concentrations were below 350 U per liter, and we measured the ef- fects on plasma IGF-I concentration, lean body mass, adipose-tissue mass, skin (dermal plus epidermal) thickness, regional bone density, and mandibular- height ratio (the height of the alveolar ridge divided by the total height of the mandible). The measurement of the mandible was included to test the hypothesis that the age-related involution of dental bone results in part from the loss of stimulation by growth hormone. 1 In ad- dition, the men were monitored for possible adverse ef- fects of the hormone by means of interviews, physical examinations, and standard laboratory tests. Nine men matched for age and with similar plasma IGF-I concen- trations served as controls. Methods Subjects Healthy men who were 61 or older and living in the community were recruited through newspaper advertisements followed by an in- terview. Entry criteria (available from the authors on request) includ- ed body weight of 90 to 120 percent of the standard for age, the abil- ity to administer growth hormone to oneself subcutaneously, and the absence of indications of major disease. Ninety-five men who an- swered the advertisements met criteria that could be ascertained by interview. Their plasma IGF-I concentrations were then determined twice at an interval of four weeks. Consistent with the results of a previous study, 13 the plasma IGF-I values in these men ranged from 100 to 2400 U per liter, with an average of 500 U per liter. Thirty- three of the men had plasma IGF-I values of less than 350 U per liter on both occasions. These 33 men were then further evaluated by a medical-history taking, physical examination, differential blood count, urinalysis, blood-chemistry tests, chest radiography, and elec- trocardiography. Twenty-six subjects (1 black and 25 white) met all the entry criteria and were enrolled in the 12-month protocol sum- marized in Table 1. Study Periods The men were seen at regular intervals and tested as shown in Ta- ble 1 during the first week of the first, third, and sixth months of the base-line period. Five men dropped out of the study during these six months (four for personal reasons and one because carcinoma of the prostate was detected). At the beginning of the seventh month, the 2 1 men who had completed the base-line period were randomly assigned to group 1 (growth hormone group) or group 2 (control group) in a ratio of 3 to 2. The randomization table was generated by a computer program Table 1 . Schedule of Tests during the Base-Line and Treatment Periods. Test Base-Lin Period ]■: Treatment Period MO 1 MO 3 MO 6 MO 7 MO MO MO MO 8 9 10 11 MO 12 Physical examination X X X X X X X X X Hematology* X X X X X X X X X Urinalysis* X X X X X X X X X Blood chemistry* X X X X X X X X X Chest radiography X X X Electrocardiography X X X Echocardiography X X X Total body potassiumf X X Skin thickness^: X X Bone density* § X X Mandibular-height ratio*H X X Plasma IGF-I X X X X X X X X X Biosynthetic growth hormone** X X X X X X *Tests included a complete blood count, hematocrit, blood indexes, and the measurement af- ter an overnight fast of plasma glucose, urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, carbon dioxide, phosphate, calcium, total protein, albumin, alkaline phosphatase, as- partate aminotransferase, lactic dehydrogenase, bilirubin, cholesterol, triglyceride high-density lipoprotein cholesterol, and glycosylated hemoglobin levels. Tests were performed at the North Chicago Veterans Affairs Medical Center laboratories. "("Total body potassium levels (lean body mass and adipose-tissue mass) were measured according to the method of Flynn et al. 1 ' 1 ^Calculated as the sum of the skin thicknesses of the right and left dorsal hand and right and left volar forearm measured with a Harpcnden caliper according to the method of Lawrence and Shuster."' §Measured according to the method of Nagraj et al. 1 ' ^Measured according to the method of Goldberg et al. Ii! ||Measurcd at Nichols Laboratory, Los Angeles, according to the method of Furlanetto et al. IS ** Administered to group 1 only. such that in each group of five men, three would be assigned to the growth hormone group and two to the control group. All 21 men (12 in group 1 and 9 in group 2) completed the treatment period and constitute the study group for this report. Their clinical character- istics are summarized in Table 2. During the first week of the sev- enth month, the men in group 1 were instructed in the subcutane- ous administration of recombinant biosynthetic human growth hormone (2.6 IU per milligram of hormone; Eli Lilly). The initial dose was 0.03 mg per kilogram of body weight, injected three times a week at 8 a.m., the interval between injections being either one or two days. A sample of venous blood for plasma IGF-I assay was obtained each month 24 hours after a growth hormone injection. If the IGF-I level was below 500 U per liter, the dose of hormone was increased by 25 percent; if the IGF-I level was above 1500 U per li- ter, the dose was reduced by 25 percent. The men in group 2 re- ceived no injections. The schedule of tests for both groups during the treatment period is shown in Table 1. At the start of the base-line period, the project dietitian instructed each man to follow a diet that furnished 25 to 30 kcal per kilogram. The distribution of kilocalories among protein, carbohydrate, and fat was approximately 15 percent, 50 percent, and 35 percent, respec- tively. At each scheduled visit shown in Table 1, the dietitian analyzed each man's diet on the basis of a 24-hour dietary recall and instructed the subjects again about the standard diet. The men were told not to alter their lifestyles (including their use of tobacco or alcohol and their level of physical activity) during the 12-month study period. The study protocol was carried out with the informed consent of each subject and with the approval of the human-research commit- tees of the Medical College of Wisconsin, the Chicago Medical School, and the Veterans Affairs Medical Centers in North Chicago and Milwaukee. Statistical Analysis The methods used to measure each response variable and the lo- cations where the tests were performed are described in Table 1. Downloaded from www.nejm.org on December 01 , 2003. Copyright© 1990 Massachusetts Medical Society. All rights reserved. Vol. 323 No. 1 EFFECTS OF HUMAN GROWTH HORMONE IN MEN — RUDMAN ET AL. Table 2. Clinical Characteristics of the Study Subjects. Grow ■ 1 Group 2 Characteristic (N = I 2) (N = 9) Median age (range) 67 (61- -73) 68 (65-81) Percent of ideal body weight — 103 (94- -120) 105 (99-117) median (range) Medical conditions (no. of subjects) Degenerative joint disease 5 2 Benign prostatic hypertrophy 3 1 Glaucoma 1 1 Cataract 2 1 Arteriosclerotic heart disease* 3 1 Gallstones 1 Kidney stone 1 1 Hiatus hernia 1 Medications (no. of subjects) Nonsteroidal antiinflammatory drug 3 1 Pilocarpine eyedrops 1 1 Gimetidine 1 *Defined as a history of myocardial infarction ( to coronary artery disease. ctrocardiograplnc abnormality ascribed The interassay coefficients of variation for the response variables were as follows: plasma IGF-I, 7.2 percent; lean body mass, 3.6 per- cent; adipose-tissue mass, 6.9 percent; skin thickness, 5.4 percent; and bone density, 2.3 percent (average of nine measured sites). P values based on two-tailed, matched-pair t-tests were calculat- ed for the comparisons between the 6-month and 12-month values in group 1 and group 2. In addition, for each response variable the 6-month value was subtracted from the 12-month value to repre- sent the change in each subject. P values based on two-tailed, un- equal-variance, independent-sample t-tests were then calculated for the comparison of the changes in response variables between groups 1 and 2. Results Clinical Observations All the men remained healthy, and none had any changes in the results of differential blood count, uri- nalysis, blood-chemistry profile, chest radiography, electrocardiography, or echocardiography during the 12-month protocol. Specifically, none had edema, fast- ing hyperglycemia (>6.6 mmol of glucose per liter), an increase in blood pressure to more than 160/90 mm Hg, ventricular hypertrophy, or a local reaction to human growth hormone, nor did their serum cholester- ol or triglyceride concentrations change significantly. In group 1, however, both the mean (±SE) systolic blood pressure and fasting plasma glucose concentration were significantly higher (P<0.05 by matched-pair t- test) at the end of the experimental period than at the end of the base-line period (127.2±5.2 vs. 119.1 ±3.6 mm Hg and 5.8±0.2 vs. 5.4±0.2 mmol per liter, re- spectively). Plasma IGF-I Concentration In group 1, the mean plasma IGF-I concentration ranged from 200 to 250 U per liter throughout the base-line period (Table 3). Within one month after the administration of growth hormone had been initiated, the mean IGF-I level rose to 830 U per liter (P<0.05), and it remained near this value for the next five months. Eight of the 12 men in group 1 required no adjustment in their initial dose of growth hormone. Two required an upward adjustment of 25 percent, and two required a downward adjustment of 25 per- cent. The mean plasma IGF-I concentration in group 2 remained in the range of 180 to 300 U per liter throughout the base-line and treatment periods. Lean Body Mass, Adipose-Tissue Mass, Skin Thickness, Bone Density, and Mandibular-Height Ratio Table 4 shows the mean values for the other re- sponse variables at the end of the base-line period (6 months) and the end of the treatment period (12 months). There was no significant change in weight in either group. In group 1, several response variables had changed significantly after 12 months. Lean body mass and the average density of the lumbar vertebrae increased by 8.8 percent (P<0.0005) and 1.6 percent (P<0.04), respectively, and adipose-tissue mass de- creased by 14.4 percent (P<0.005). The sum of skin thicknesses at four sites increased 7.1 percent (P = 0.07). The small average change in lumbar vertebral bone density (only 0.02 g per square centimeter) was statistically significant because of very little variability in individual results. The bone density of the radius and proximal femur and the ratio of the height of the alveolar ridge to total mandibular height did not change significantly. In group 2 none of these variables changed significantly. The change in the lean body mass was significantly greater in group 1 than in group 2 (P<0.018), but the differences in changes in skin thickness and adipose-tissue mass between groups did not reach statistical significance in this small series (P = 0.10 and 0.13, respectively). Table 3. Effect of the Administration of Human Growth Hormone on Plasma IGF-I Concentrations in Healthy Older Men.* Group Plasma IGF-I BASE-LINE PERIOD TREATMENT PERIOD mo 1 mo 3 mo 6 mo 7 mo 8 units per liter mo 9 mo 10 mo 1 1 mo 12 Group 1 240 ±86 230+97 230±66 830 + 339t 680+180f 720 + 350J 810+3051 810+192t 910+3121 Group 2 240 ±69 240+126 240+108 200+126 220+123 240+177 180±126 240+186 300 ±201 *Values arc r ncans ±SD. tP<0.05 for the eompariso! l between groups. Downloaded from www.nejm.org on December 01 , 2003. Copyright© 1990 Massachusetts Medical Society. All rights reserved. THE NEW ENGLAND JOURNAL OF MEDICINE July 5, 1990 Table 4. Effect of the Administration of Human Growth Hormone on Weight, Lean Body Mass, Adipose-Tissue Mass, Skin Thickness, and Bone Density in Healthy Older Men.* Variable Group End of Base-Line Period End of Treatment Period P Value! DlFFERE nce in Changes^ Weight (kg) 2 77.2+11.4 83.3 + 11.1 78.2+12.1 83.3 + 9.7 0.26 0.97 + 1.0 -1.4 to +3.4) Lean body mass (kg) 2 53.0 + 7.4 54.2 + 7.1 57.7 + 9.1 55.2 + 7.3 0.0005 0.17 + 3.7 + 0.7 to +6.6) Adiposc-tissuc mass (kg) 2 24.1+5.0 29.0+6.4 20.6 + 5.6 28.0±4.0 0.05 0.13 -2.4 -5.7 to +0.8) Sum of skin thickness at four sites (mm) 2 9.9+1.2 9.3+0.9 10.6+1.5 9.23±0.80 0.07 0.69 +0.8 -0.1 to +1.7) Bone density (g/cm 2 ) Mid-shaft radius 2 0.74+0.10 0.76+0.10 0.74+0.12 0.71 + 0.07 0.85 0.09 + 0.04 -0.02 to +0.10) Distal radius 2 0.37+0.07 0.34±0.04 0.36±0.08 0.33±0.05 0.12 0.26 -0.004 -0.03 to +0.02) Average, lumbar vertebrae 1—4 2 1.23+0.12 1.29+0.25 1.25 + 0.13 1.29±0.26 0.01 0.61 +0.006 ( -0.04 to +0.05) Ward's triangle 2 0.70+0.14 0.70+0.17 0.69±0.13 0.70+0.17 0.15 0.69 -0.018 -0.08 to +0.05) Greater trochanter 2 0.85+0.13 0.81+0.15 0.85 + 0.13 0.81 + 0.13 0.72 0.55 + 0.007 ( -0.05 to +0.03) Femoral neck 2 0.92+0.15 0.89+0.14 0.91+0.14 0.85±0.14 0.53 0.11 -0.029 -0.08 to +0.03) Mandibular-hcight ratio 2 0.45+0.15 0.47+0.12 0.46 + 0.11 0.47 + 0.12 0.87 0.98 -0.00.3 -0.07 to +0.06) *Plus-minus values are means ±SD. |P values are for the change from base line, by matehed-pair t-test. iThe difference in changes (12-month value minus 6-month value) is the average change in group 1 minus the average change in group 2. Values in parentheses are 95 percent confidence intervals, calculated by independent-sample, unequal- variance t-tests. Discussion The 21 men studied were representative of the ap- proximately one third of all men 60 to 80 years old who have plasma IGF-I concentrations of less than 350 U per liter (as compared with a range of 500 to 1500 U per liter in healthy men 20 to 40 years old). 4 Our findings cannot be generalized to the approximately two thirds of all men over 60 who have plasma IGF-I concentra- tions of more than 350 U per liter or to women of a similar age. Furthermore, our entry criteria focused the study on an overtly healthy subgroup of older men. In the absence of obesity, 4 below-normal weight, 20 or liver disease, 21 a plasma IGF-I concentration of less than 350 U per liter in older men generally signifies that they secrete very little growth hormone. 4 To verify this explanation for the low plasma IGF-I concentration in these men, it would be necessary to measure serum growth hormone levels at frequent intervals for 24 hours or to determine the 24-hour urinary excretion of growth hormone. We did not do this, but Ho et al. found that the 24-hour integrated serum growth hormone lev- el was markedly lower in the men over 55 than in men 18 to 33 years old. 22 An alternative explanation for a low plasma IGF-I concentration is decreased production of plasma IGF-I binding proteins. Most of the IGF-I plas- ma is bound to these proteins, but their concentrations vary little in healthy people who eat a normal diet. In the 12 men in group 1, initially low plasma IGF-I concentrations were raised to the normal range for young adult men by the dose of growth hormone administered, with no evidence of tachyphylaxis or hor- mone resistance. The dose, approxi- mately 0.03 mg per kilogram three times a week, was based on pub- lished estimates of the rate of growth hormone secretion in young men 23 and was comparable to or smaller than doses given previously to children with growth hormone deficiency 24 ' 25 and young adults. 10 " 13 The plasma IGF-I responses to this dose in these older men were similar in magnitude to those in younger people. That "replacement" rather than pharmacologic doses were be- ing administered was confirmed by the plasma IGF-I measurements, which remained within the range for healthy young adults (500 to 1500 U per liter) throughout the treatment period (Table 3). We conclude that in aging men with low plasma IGF-I concentrations hepatic responsive- ness to human growth hormone is not impaired, and the decline in plasma IGF-I concentrations in such men results from growth hormone deficiency rather than growth hor- mone resistance. The increase in plasma IGF-I levels that occurs when growth hormone is administered to children with growth hormone deficiency reflects not only augmented hepatic production of IGF-I, but also increased production of one of the binding proteins that transport IGF-I. 26 The extent to which the pro- duction of IGF-I binding protein is increased by the administration of growth hormone has not yet been studied in adults. At the beginning of our study, adverse reactions to human growth hormone were thought to be unlikely because physiologic doses were being used. Further- more, similar or larger doses have not caused undes- ired reactions in children or young adults. 10 " 14 ' 23 Never- theless, it remained possible that this dose, when given for six months to older subjects, might cause some manifestation of hypersomatotropism, such as edema, hypertension, diabetes, or cardiomegaly. 2 '" 29 Although none of these conditions developed, there were small increases in the mean systolic blood pres- sure and fasting plasma glucose concentration of the group of men who received growth hormone. The magnitude of the increases in lean body mass and the decreases in adipose-tissue mass (8.8 and -14.2 percent above and below base line, respectively) in the aging men who received human growth hormone for six months was similar to the magnitude of these re- Downloaded from www.nejm.org on December 01 , 2003. Copyright© 1990 Massachusetts Medical Society. All rights reserved. Vol. 323 No. 1 EFFECTS OF HUMAN GROWTH HORMONE IN MEN — RUDMAN ET AL. sponses in children 8,9 and young adults 10 " 13 treated with similar or lower doses for three to six months, a comparison that provides further evidence that tissue responsiveness to growth hormone and IGF-I is not al- tered in older men. Until now, the evidence for such a conclusion came only from short-term nitrogen-bal- ance experiments. 14,30 " 32 Salomon et al. reported that the administration of human growth hormone in a dose of 0.49 unit per kilo- gram per week (0.19 mg per kilogram per week) for six months to adults 20 to 50 years old who had growth hormone deficiency lowered the serum cholesterol con- centration significantly. 13 Serum cholesterol concentra- tions did not change in our study, in which the dose of growth hormone was about half as large (0.9 mg per kilogram per week). The divergent results could reflect differences in the subjects' ages, the degree of growth hormone deficiency, the dose of hormone, or all three. In rodents, the increase in lean body mass in re- sponse to growth hormone is due to increases in the volume of skeletal muscle, skin, liver, kidney, and spleen. 1,7 In young human subjects, an enlargement of muscle and kidney induced by growth hormone has been documented 8 " 12 ; other organs have not yet been assessed. The reduction in adipose-tissue mass when children with growth hormone deficiency are treated with human growth hormone is associated with a re- distribution of adipose tissue from abdominal to pe- ripheral areas. 31 It is not known, however, whether the increase in lean body mass and the decrease in adi- pose-tissue mass are qualitatively as well as quantita- tively similar in old and young human subjects. Biosynthetic human growth hormone had no detect- able effect on the bone density of the radius or proxi- mal femur in the aging men, but it increased the den- sity of the lumbar vertebrae by about 1.6 percent. Although the decrease in bone density with advancing age in men may be due in part to diminished secretion of growth hormone, 1,33 longer periods of administration of human growth hormone will be required before a fi- nal conclusion can be drawn regarding its efficacy in reversing that decrease. A similar interpretation applies to the lack of increase in the mandibular-height ratio. The findings in this study are consistent with the hy- pothesis that the decrease in lean body mass, the in- crease in adipose-tissue mass, and the thinning of the skin that occur in older men are caused in part by re- duced activity of the growth hormone-IGF-I axis, and can be restored in part by the administration of human growth hormone. 1,2 The effects of six months of human growth hormone on lean body mass and adipose-tissue mass were equivalent in magnitude to the changes in- curred during 10 to 20 years of aging. 1,34,35 Among the questions that remain to be addressed are the follow- ing: What will be the benefits and what will be the na- ture and frequency of any adverse effects when larger numbers of elderly subjects and other doses of human growth hormone are studied? What organs are respon- sible for the increase in lean body mass, and do their functional capacities change as well? Only when such questions are answered can the possible benefits of hu- man growth hormone in the elderly be explored. Since atrophy of muscle and skin contributes to the frailty of older people, the potential benefits of growth hormone merit continuing attention and investigation. We are indebted to Dr. Ruth Hartmann, Milwaukee Veterans Af- fairs Medical Center, for assistance in the preparation of this report. References 1 . Rudman D. Growth hormone, body composition, and aging. J Am Geriatr Soc 1985; 33:800-7. 2. Meites J. Neuroendocrine biomarkers of aging in the rat. Exp Gerontol 1988; 23:349-58. 3. Finkelstein JW, Boyar RM, Roffwarg HP, Kream J, Hellman L. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 1972; 35:665-70. 4. Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Im- paired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest 1981; 67:1361-9. 5. Clemmons DR, Van Wyk JJ. Factors controlling blood concentration of so- matomedin C. Clin Endocrinol Metab 1984; 13:113-43. 6. Florini JR, Prinz PN, Vitiello MV, Hintz RL. Somatomedin-C levels in healthy young and old men: relationship to peak and 24-hour integrated lev- els of growth hormone. I Gerontol 1985; 40:2-7. 7. van Buul-Offers S, Van den Brande JL. The growth of different organs of normal and dwarfed Snell mice, before and during growth hormone therapy. Acta Endocrinol 1981; 96:46-58. 8. Parra A, Argote RM, Garcia G, Cervantes C, Alatorre S, Perez-Pasten E. Body composition in hypopituitary dwarfs before and during human growth hormone therapy. Metabolism 1979; 28:851-7. 9. van der Werff ten Bosch JJ, Bot A. Effects of human pituitary growth hor- mone on body composition. Neth J Med 1987; 30:220-7. 10. Crist DM, Peake GT, Mackinnon LT, Sibbitt WL Jr, Kraner JC. 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